HYPOGAMMAGLOBULINEMIA OCCURS IN FAS-DEFICIENT MRL-LPR MICE FOLLOWING DELETION OF MHC CLASS-II MOLECULES

Fas (CD95)-mediated apoptosis in B and T cells is deficient in both hu man autoimmune lymphoproliferative syndrome and in MRL-lpr mice, a mod el for systemic lupus erythematosis (SLE). Autoimmune disease in these mice is associated with polyclonal B cell activation, increased serum immunoglobulin and autoantibodies. In non-autoimmune mice MHC class I I is not required for normal serum immunoglobulin expression, and prev iously we have shown using MHC class II-deficient MRL-lpr mice (MRL-lp r Ab-/-) that generation of specific antibodies to DNA requires MHC cl ass II-directed T cell help. In contrast, in the present study we demo nstrate that MRL-lpr Ab-/- mice also have a profound reduction of tota l serum immunoglobulin levels, suggesting abnormal polyclonal regulati on of B cells by MHC class II-directed T cells occurs in the autoimmun e MRL-lpr strain. This abrogation of immunoglobulin production does no t occur in MHC class II-deficient non-obese diabetic (NOD) mice, nor i n MHC class I-deficient NOD or MRL-Epr mice. Reduced immunoglobulin le vels in MRL-lpr Ab-/- mice were not due to a lack of B cells or to an increased loss of circulating immunoglobulin, but were associated with reduced numbers of surface Igc-positive B cells. These results define a general abnormal regulation of B cells in MRL-lpr mice through a pr ocess requiring MHC class II, and suggest that Fas deficiency may allo w expansion of totally T-dependent B cells.